During the course of chemotherapy of human cancers, variants which are resistant to multiple drugs frequently arise. We have been investigating the genetic and biochemical basis for this pleiotropic resistance of human tumor cells to chemotherapeutic agents. A model system using the cultured KB cell, a human carcinoma cell line, has been developed in which mutant cells selected for resistance to high levels of colchicine have also been found to be resistant to adriamycin, vincristine, vinblastine, puromycin and actinomycin-D. This multiple drug-resistance has been demonstrated to be a co-dominant genetic characteristic in somatic cell hybrids. Resistance to colchicine has been successfully transferred to sensitive human and mouse cells using DNA derived from these drug-resistant human cells. Uptake of several of the drugs involved in the multiple drug-resistance phenotype has been shown to be reduced in the KB cells. Drug-resistance correlates with the appearance of a family of high molecular weight glycoproteins on the cell surface detected by a monoclonal antibody.